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FDA’s supplement warning system has deadly limitations

By Ryan Felton

In August 2011 a Colorado woman was rushed to an emergency room in cardiac arrest a day after her husband injected her with a mineral salt called cesium chloride.

For the better part of a year, the 61-year-old had taken a dietary supplement containing cesium as an alternative treatment for breast cancer until a nutritionist recommended injecting a dose instead.

Though ER doctors were at first able to stabilize her condition, the woman was eventually discharged to hospice care in a “neurovegetative state,” according to a case report published in the Journal of Alternative and Complementary Medicine. She died three days later.

Her use of cesium probably caused her death, the report’s authors said.

Cesium chloride

Seven years later, the consumer advocacy group Public Citizen petitioned the Food and Drug Administration to ban all dietary supplements containing cesium chloride or other cesium salts. It pointed to case reports of 16 patients who had died, suffered cardiac arrest, or experienced other serious adverse events after using the products.

In early February of this year, the FDA agreed to issue a public health advisory warning consumers about the risks of cesium chloride supplements. And it has acknowledged that the substance is associated with significant safety risks.

Still, the agency denied Public Citizen’s request to ban cesium chloride products, in part because only a few adverse events related to them show up in a little-known FDA database that the agency relies on to police the nation’s $46 billion supplement industry.

That database, called CAERS, is meant to alert the agency to potentially dangerous supplements.

But the cesium episode illustrates serious shortcomings in a warning system that doesn’t adequately protect the public, a Consumer Reports investigation has found. As long ago as 2001, when the FDA handled reports about adverse events caused by dietary supplements in a precursor to CAERS, a report by the inspector general of the Department of Health and Human Services called the agency’s system (PDF) an “inadequate safety valve” to protect consumers.

Two decades later, that remains the case even with CAERS in place. That’s according to CR’s review of thousands of pages of FDA reports and records obtained through public records requests, and interviews with more than a dozen consumer advocates and experts on supplements.

Michael Carome, M.D., director of health research at Public Citizen, says that the regulatory structure for dietary supplements is flawed. And he says that relying on reports submitted after a product is on the market into a database known to have issues “puts consumers at risk.”

A Flawed System

CAERS, or the Center for Food Safety and Applied Nutrition Adverse Event Reporting System, is a collection of complaints about dietary supplements and other products submitted by consumers, healthcare practitioners, and manufacturers.

Consumers and doctors submit the reports voluntarily. Manufacturers must submit them whenever they receive reports about consumers who experienced serious adverse events, including death or hospitalization, after taking one of their supplements.

The reports can’t, on their own, establish a cause-and-effect link between an incident and a product. Rather, the agency scours the database, using algorithms to detect signals of potential safety problems.

But the system is plagued by problems, starting with underreporting. The agency receives just an estimated 2 percent of adverse event reports related to supplements annually. As a result, it can take years for the FDA to build a case that a supplement is unsafe and, as with cesium chloride, even consider getting it removed from the market.

Unlike with drug monitoring, the FDA doesn’t have to alert the public when it investigates a potential problem with a supplement. And though the FDA made CAERS public a few years ago, it has done little to make the data useful to consumers. In only a few cases has CAERS clearly played a major role in the recall of dietary supplements.

Even the FDA acknowledges the challenges of using the database, a reality underscored in a February 2020 memo obtained by CR related to the agency’s handling of cesium chloride supplements. A staffer not only pointed to the small number of reports linked to the products—which wasn’t surprising given the known problem of underreporting—but also said those reports often lacked crucial information about the people who reported problems, including their age, contact information, and relevant medical history.

Despite its shortcomings, CAERS remains the FDA’s main tool to regulate the estimated 80,000 supplements sold today. That’s because unlike pharmaceutical drugs, which require extensive testing before they can be made available for sale, federal regulations don’t require supplement manufacturers to prove that their products are safe before going to market.

The FDA’s role in identifying and regulating potentially dangerous supplements generally comes after consumers have already purchased and taken them. And while the agency does test a small number of supplements to identify possible adulterants and conducts a few inspections of manufacturing facilities, it mostly relies on CAERS to detect potential problems.

Nathan Arnold, an agency spokesperson, says that CAERS remains a “useful tool” for the agency despite its limitations.

“These reports require careful review and interpretation, and conclusions should be made within the context of all available safety data about a product, with CAERS data being one piece,” Arnold says. “The FDA also monitors the safety of products through other sources, including information from manufacturers and healthcare providers.”

And, he says, if it finds a supplement that’s unsafe or violates the law, the agency “takes action as appropriate, based on public health priorities and available resources.”

Andrea Wong, Ph.D., senior vice president of scientific and regulatory affairs at the Council for Responsible Nutrition, a supplement industry group, says CAERS works well for consumers. “We fully support the system that’s in place,” she says.

But some advocates and government watchdogs say CAERS is too limited to protect consumers. “The FDA’s adverse event reporting system may weed out a few dangerous supplements, but only after they’ve been on sale, sometimes for many years,” says Chuck Bell, programs director in CR’s advocacy division, which has pushed for years to reform dietary supplement regulation.

Slow to Act

One example of the system’s shortcomings concerns Hydroxycut, a weight loss supplement first popularized in the early 2000s.

In 2004 the FDA banned ephedra—the active ingredient in Hydroxycut—after it received thousands of adverse event reports that included a number of heart attacks, strokes, and deaths among people who took supplements with the ingredient.

But rather than withdrawing Hydroxycut from the market, its manufacturer simply reformulated the product. Despite the reformulation, reports of liver failure continued.

Martin Robertson, a Maryland resident, first started purchasing Hydroxycut in November 2008 and used it as directed, according to a lawsuit he later filed. But a few months later, he was given a diagnosis of liver damage and kidney failure, the lawsuit says, and he spent more than a month in a hospital. He blamed Hydroxycut.

“As a direct and proximate result of using Hydroxycut Regular Rapid Release Caplets,” the lawsuit says, Robertson “suffered severe mental and physical pain and suffering and has sustained permanent injuries and emotional distress.”

Ioavate, the maker of Hydroxycut, denied the claims in court. The case was eventually settled.

It took the FDA seven years to compile enough reports—23 in all, including one death—to determine that Hydroxycut was causing the liver injuries. It warned consumers to stop taking it and got the manufacturer to agree to recall the product line.

The FDA’s evaluation couldn’t determine which ingredient in Hydroxycut was causing the problem. But the agency ultimately concluded “that the ingestion of the dietary supplement, Hydroxycut, presents a severe, potentially life-threatening, hazard to some users.”

In a 2013 report, the Government Accountability Office, a government watchdog, pointed to Hydroxycut as an example of how difficult it is for the FDA to use CAERS (PDF) to accumulate “enough evidence to discern a clear relationship” between a product and a reported health problem.

“Most [adverse event reports] do not initiate or support such actions because it is difficult to establish causality between the product and the health problem based on the limited information in an AER,” the report said.

‘Woefully Inadequate’ System

That the FDA’s supplement surveillance system is inadequate is also borne out by its handling of another supplement that was popular about a decade ago, OxyElite Pro.

Manufactured by USPlabs in Dallas, the supplement contained an artificial stimulant called DMAA, an amphetamine derivative linked to increased blood pressure and heart attacks.

In late 2011 the Department of Defense ordered supplements containing DMAA to be removed from stores on military bases after it said the stimulant was a possible factor in the deaths of four soldiers. A subsequent analysis of the CAERS database, captured in a study by FDA staffers, showed that the agency had received several reports citing products containing DMAA the previous year.

In April 2012 the FDA issued warning letters to firms that manufactured supplements containing DMAA, which led them to remove the products from the marketplace.

But USPlabs continued to sell its product, reformulating OxyElite Pro with a previously unused dietary supplement ingredient called aegeline as it phased out DMAA.

In September 2013 healthcare practitioners in Hawaii identified several cases involving adults who developed acute or fulminant nonviral hepatitis after taking OxyElite Pro, and notified the FDA. The following month, the Hawaii Department of Public Health had identified 21 cases involving adults who developed liver disease after taking OxyElite Pro, and submitted reports about them to CAERS for the FDA to review and determine whether the product was causing the injuries.

The FDA reviewed an additional 12 cases filed in CAERS involving consumers from other states, and determined that taking OxyElite Pro likely contributed to liver injury in those who consumed it. USPlabs agreed to recall the product, saying it was a precautionary measure.

Daniel Fabricant, Ph.D., who led the FDA supplements office at the time and is now CEO of the industry group Natural Products Association, says the agency responded in a timely way, evaluating the reports as soon as they were received.

But a subsequent study by FDA staffers published in the medical journal Public Health Reports highlighted a “significant lag” between the time an incident occurred and when it was reported, and said the value of the system “depends largely on the extent to which potential reporters employ the system.”

A 2014 article in The New England Journal of Medicine by Pieter Cohen, M.D., an assistant professor of medicine at Harvard Medical School who has studied supplements extensively, was more blunt.

“The FDA’s delayed response—with its life-threatening consequences—is attributable to our woefully inadequate system for monitoring supplement safety,” he wrote.

Too Little to Work With

After the ephedra ban, Congress tried to improve the adverse reporting system for supplements in 2006 by mandating that companies submit reports they receive.

But the law required only that they submit “serious” ones, such as those resulting in death, hospitalization, or a “life-threatening experience.” The only way for the FDA to verify that companies are submitting those reports, though, is by conducting an audit of their reports during an inspection, something that happens infrequently.

Of equal concern were reporting rates for adverse events that were estimated to be around 2 percent, according to a 2017 study in Annals of Pharmacotherapy written by FDA staffers.

In late 2016 the FDA once again tried to promote the submission of more reports, this time by making it possible not just for people to submit them but also for consumers, academics, and others to examine the database itself. The agency hoped that increased access would translate into more people submitting reports.

But since CAERS went public, the FDA has actually received fewer adverse event reports associated with supplements, the agency confirmed, from 5,355 in 2016 to 3,576 in 2017, and dropping to 2,899 in 2018.

Arnold, the FDA spokesperson, says “The FDA cannot speculate why data may be fluctuating, but regardless, CAERS continues to be a useful tool for its intended purposes.”

Harvard’s Cohen says the agency isn’t doing enough to follow up. “Year after year there has been no substantial enforcement action by the FDA to remove dangerous supplements from the marketplace based on adverse event reports,” he says. “Rational consumers and their physicians could reasonably conclude that it is fruitless to submit more reports to an agency that is not following up on the reports.”

Unhelpful Data

An examination of the current publicly available database by CR suggests that it still has little utility to consumers, a critique leveled in the inspector general’s report from two decades ago.

For example, a consumer reviewing the database today might note that a product called Super Beta Prostate appears to be one of the most frequently cited supplements in CAERS, with 1,090 reports, according to a CR review.

(It’s possible that other supplements may have more reports because there are often numerous names listed for a product, complicating independent analysis of the database. Even the FDA says an analysis requires “making assumptions.”)

Marketed as an aid for men with urinary frequency problems, Super Beta Prostate contains an ingredient called beta-sitosterol, which studies suggest may help improve urine flow in men with an enlarged prostate.

Among the research conducted to date, CR found no convincing evidence that beta-sitosterol or Super Beta Prostate is unsafe for consumption. CR even conducted some limited testing of the supplement to see if it was adulterated with prescription drugs such as tamsulosin (Flomax) and sildenafil (Viagra), which are sometimes used to treat an enlarged prostate. A drug in a supplement could interact dangerously with other medications. And sildenafil, in particular, has previously been found in some supplements. CR’s tests didn’t find those specific adulterants.

Given the way reports are collected in the database, a large raw total doesn’t necessarily indicate a problem. “The number is not what drives the cases,” says Fabricant at the Natural Products Association. “What drives the cases is the quality of [reports].”

Still, an examination of FDA records on Super Beta Prostate, obtained through a Freedom of Information Act request, offers insight into how the FDA seeks to determine whether there’s a causal relationship between a product and adverse events.

In 2016, records show, FDA staffers mined CAERS and detected a signal potentially tying Super Beta Prostate to reports of hematuria, or blood in urine, prompting the agency to investigate.

But the data was incomplete. The FDA requires only that reports include the product name, the possible harm, the name of the person filing the complaint, and, when submitted by a manufacturer, the name of the patient and contact information for the person or company filing the complaint. (The names aren’t included in the public-facing database.)

That could factor into incomplete, confusing submissions. For example, only about a third of the Super Beta Prostate reports identify the consumer’s age, according to CR’s analysis. And documents obtained by CR suggest that the FDA wasn’t even able to posit a theory as to why the product might cause blood in urine—if it was at all—even though it had several hundred reports on file to review.

“We have no theory to explain why the effect (if it exists) is so specific to the genitourinary tract,” an FDA investigator said in a document.

One possible reason is that blood in the urine is relatively common among men with enlarged prostates, according to experts and the supplement firm New Vitality, which makes Super Beta Prostate.

New Vitality, based in New York, added that the high number of reports linked to its product in the CAERS database is because the company has a policy of overreporting adverse events to the FDA, not just ones considered serious, and that the rate is actually low compared with the volume of product they sell.

The company also says that because its business model has relied heavily on direct-to-consumer sales, event reporting occurs at a higher rate than for products sold through third parties. And it pointed out that after an investigation, the FDA didn’t conclude that the products posed a safety risk to the public.

New Vitality also reinforced to CR that Super Beta Prostate has an “unblemished safety record.”

Inconsistent Regulations

In October 2016 records obtained by CR suggested that the FDA’s investigation of Super Beta Prostate ended with the agency taking no enforcement action.

But contrary to how the FDA handles prescription drugs, it never alerted the public about the adverse event reports or its investigation. (When asked by CR, an FDA spokesperson repeatedly declined to comment about the agency’s effort with Super Beta Prostate.)

By law the FDA has to conduct routine screenings of FAERS, the drug counterpart to CAERS, and then publicize any “potential signal of a serious risk” associated with a drug. After the agency evaluates signals from that database, it determines whether the drug is associated with the risk, and, if so, what regulatory action is required—and then publishes an update of the findings on its website.

With supplements, however, the FDA isn’t required to publicize the results of its investigation or even tell the public it conducted one. The FDA didn’t answer CR’s question about why it doesn’t use the same approach for both CAERS and FAERS.

Wong, at the Council for Responsible Nutrition, says the system works well for consumers because the FDA would notify them if CAERS research uncovered a risk with a supplement.

“FDA’s already analyzed the information, and based on their scientific expertise has determined that information is relevant for consumers to be aware of,” Wong says.

But the reports in CAERS are public and could also be reviewed by academics and researchers. And consumers overwhelmingly presume that dietary supplements are safe or they wouldn’t be on the market. So if there are emerging reports about potential hazards, consumers would want to know that information as quickly as possible, says CR’s Bell.

Publicizing the investigation of a signal found in CAERS—especially one that ends with the agency finding no regulatory action is necessary—could also provide additional assurances to consumers about the safety of a product, he says.

Bell adds that a better system would be one that mandates that supplements, like drugs, be proved to be safe and effective before consumers can buy them. “It would be far preferable to require safety testing and FDA approval up front,” he says. “The current system, in effect, benefits the supplement companies far more than it benefits consumers.”

How to Fix the Alarm System

If the FDA wants to gather more reports of adverse events, consumer advocates suggest amending the 2006 law to require supplement makers to submit reports of incidents it receives about all events, not just ones deemed serious.

“It’s always good to have more data, right?” says Peter Lurie, a former FDA official and president of the Center for Science in the Public Interest, a consumer watchdog in Washington, D.C. “What you would worry about is, if it is in the hands of the company to make a determination if something is serious, there’s always the incentive to underreport.”

Another suggestion is for the FDA to better coordinate with other groups or agencies that receive reports of adverse events linked to dietary supplements. For example, between 2008 and 2010, poison control centers received an estimated 1,000 more reports of events related to dietary supplements than the FDA had, according to the 2013 Government Accountability Office study.

The GAO pointed out that the FDA could benefit from such a move. The FDA considered a plan to obtain the data but said it couldn’t afford it in the end. Consumer advocates and researchers have continued to suggest that the FDA explore the option.

For consumers who have an adverse event after taking a supplement, after seeking medical attention they should file a report about the incident with the FDA, and encourage their healthcare provider to do so as well. They should also contact the manufacturer, which is required to tell the FDA about it if the event is serious.

And tell your doctor about whatever supplements or drugs you’re already taking. “It’s very important that we understand this,” says Robert Nam, M.D., a urologist and professor of surgery at the University of Toronto. “With that information, the physician can at least inform patients of possible links and possible effects.”
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Credit: Consumer Reports